The peptide Big Endothelin, found in endothelium cells, is cleaved by the enzyme Endothelin Converting Enzyme (ECE) to produce the peptide Endothelin. Endothelin is a 21 amino acid vasoconstrictor and is produced by endothelium cells, mesangial, kidney and epithelial cells and by various human cancer cell lines and human macrophages.
Biologically, endothelin has effects on vascular smooth muscle, nonvascular smooth muscle, heart, nervous tissue, kidney and adrenal glands. Endothelin constricts arteries and veins, increases mean arterial blood pressure, decreases cardiac output, increases cardiac contractility in vitro, stimulates mitogenesis in vascular smooth muscle cells in vitro, contracts vascular smooth muscle including guinea pig trachea, human urinary bladder strips and rat uterus in vitro, increases airway resistance in vivo, induces formation of gastric ulcers, stimulates release of atrial natriuretic factor in vitro and in vivo, increases plasma levels of vasopressin, aldosterone and catecholamines, inhibits release of renin in vitro and stimulates release of gonadrotropin in vitro. See, for example, PCT patent application publication No. Wo 92/13545.
Possible indications for use of inhibitors of production of endothelin include treatment of cardiovascular diseases (e.g., myocardial ischemia, congestive heart failure, arrhythmia, unstable angina and hypertension); bronchoconstriction (pulmonary hypertension and asthma); neuronal action disorders (cerebral vasospasm and subarachnoid hemorrhage); endocrine disorders (pre-eclampsia); renal disease (acute/chronic renal failure); vascular disorders (atherosclerosis, Buergers disease, Takayasu's arteritis, Raynaud's phenomenon and complications in diabetes); cancer (especially pulmonary carcinoma; gastric mucosal damage (gastrointestinal disorders); and endotoxic shock and septicemia. See J. Med. Chem. 35(9): 1493-1508 (1992); Neurology 42:25-31 (1992); and Drug Development Research 26:361-387 (1992).